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A patient with type 2A von Willebrand disease and a long history of gastrointestinal (GI) bleeding is presented, in whom no abnormality was found on sequencing the von Willebrand factor gene at the DNA level. Subsequent RNA analysis revealed him to be heterozygous for a T-C substitution at nucleotide 4,883, a mutation previously described and associated with type 2A von Willebrand disease. This illustrates the value of a dual DNA/ RNA approach to genetic investigations of highly polymorphic genes. GI bleeding from angiodysplasia is a feature of von Willebrand disease, particularly type 2A. Proactive management with definitive diagnosis of angiodysplasia and ablative treatment where feasible is recommended to stop bleeding symptoms and minimize exposure to blood products.

Context: Few cardiovascular outcome data are available for blacks with hypertension treated with angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers (CCBs)., Objective: To determine whether an ACE inhibitor or CCB is superior to a thiazide-type diuretic in reducing cardiovascular disease (CVD) incidence in racial subgroups., Design, Setting, and Participants: Prespecified subgroup analysis of ALLHAT, a randomized, double-blind, active-controlled, clinical outcome trial conducted between February 1994 and March 2002 in 33,357 hypertensive US and Canadian patients aged 55 years or older (35% black) with at least 1 other cardiovascular risk factor., Interventions: Antihypertensive regimens initiated with a CCB (amlodipine) or an ACE inhibitor (lisinopril) vs a thiazide-type diuretic (chlorthalidone). Other medications were added to achieve goal blood pressures (BPs) less than 140/90 mm Hg., Main Outcome Measures: The primary outcome was combined fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI), analyzed by intention-to-treat. Secondary outcomes included all-cause mortality, stroke, combined CVD (CHD death, nonfatal MI, stroke, angina, coronary revascularization, heart failure [HF], or peripheral vascular disease), and end-stage renal disease., Results: No significant difference was found between treatment groups for the primary CHD outcome in either racial subgroup. For amlodipine vs chlorthalidone only, HF was the only prespecified clinical outcome that differed significantly (overall: relative risk [RR], 1.37; 95% confidence interval [CI], 1.24-1.51; blacks: RR, 1.46; 95% CI, 1.24-1.73; nonblacks: RR, 1.32; 95% CI, 1.17-1.49; P<.001 for each comparison) with no difference in treatment effects by race (P = .38 for interaction). For lisinopril vs chlorthalidone, results differed by race for systolic BP (greater decrease in blacks with chlorthalidone), stroke, and combined CVD outcomes (P<.001, P = .01, and P = .04, respectively, for interactions). In blacks and nonblacks, respectively, the RRs for stroke were 1.40 (95% CI, 1.17-1.68) and 1.00 (95% CI, 0.85-1.17) and for combined CVD were 1.19 (95% CI, 1.09-1.30) and 1.06 (95% CI, 1.00-1.13). For HF, the RRs were 1.30 (95% CI, 1.10-1.54) and 1.13 (95% CI, 1.00-1.28), with no significant interaction by race. Time-dependent BP adjustment did not significantly alter differences in outcome for lisinopril vs chlorthalidone in blacks., Conclusions: In blacks and nonblack subgroups, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary CHD or any other prespecified clinical outcome, and diuretic-based treatment resulted in the lowest risk of heart failure. While the improved outcomes with chlorthalidone were more pronounced for some outcomes in blacks than in nonblacks, thiazide-type diuretics remain the drugs of choice for initial therapy of hypertension in both black and nonblack hypertensive patients.

Factor VII (FVII) plays a critical role in the initiation of blood coagulation, and patients with dysfunctional or reduced levels of this protein are susceptible to mucosal bleeding. There is poor correlation between the clinical presentation and the phenotypic data; and in cases of a mild bleeding tendency, mild to moderate reductions in both FVII antigen and activity may be overlooked. The prevalence of FVII deficiency may therefore be underestimated. Polymorphic differences throughout the FVII gene are associated with variations in plasma FVII antigen and activity levels. This study highlights the significance of mild FVII deficiency, and examines the importance of seven previously published polymorphisms in such patients.

A cross-sectional dose-response relationship between sodium intake and blood pressure (BP) has been demonstrated, but evidence for a graded longitudinal effect is limited. Evaluation of BP response to sodium reduction was assessed in a 3-year lifestyle dietary intervention trial. BP changes at 18 and 36 months after enrollment were analysed according to concurrent quantitative changes in sodium excretion and by categories of success in sodium reduction among 1157 men and women, ages 30-54 years, with a diastolic BP (DBP) 83-89 mmHg, systolic BP (SBP) <140 mmHg, body weight 110-165% of sex-specific standard weight, and valid baseline urinary sodium excretion. Participants were randomized to a Sodium Reduction intervention (n=581) or Usual Care (n=576). From a 187 mmol/24 h baseline mean sodium excretion, net decreases were 44 mmol/24 h at 18 months and 38 mmol/24 h at 36 months in Sodium Reduction vs Usual Care. Corresponding net decreases in SBP/DBP were 2.0/1.4 mmHg at 18 months, and 1.7/0.9 mmHg at 36 months. Significant dose-response trends in BP change over quintiles of achieved sodium excretion were seen at both 18 (SBP and DBP) and 36 (SBP only) months; effects appeared stronger among those maintaining sodium reduction. Estimated SBP decreases per 100 mmol/24 h reduction in sodium excretion at 18 and 36 months were 2.2 and 1.3 mmHg before and 7.0 and 3.6 mmHg after correction for measurement error, respectively. DBP changes were smaller and nonsignificant at 36 months. In conclusion, incremental decreases in BP with lower sodium excretion were observed in these overweight nonhypertensive individuals.

Sodium reduction is efficacious for primary prevention of hypertension, but the feasibility of achieving this effect is unclear. The objective of the paper is detailed analyses of adherence to and effects of the sodium reduction intervention among overweight adults in the Trials of Hypertension Prevention, Phase II. Sodium reduction (comprehensive education and counselling about how to reduce sodium intake) was tested vs no dietary intervention (usual care) for 36-48 months. A total of 956 white and 203 black adults, ages 30-54 years, with diastolic blood pressure 83-89 mmHg, systolic blood pressure (SBP) <140 mmHg, and body weight 110-165% of gender-specific standard weight were included in the study. At 36 months, urinary sodium excretion was 40.4 mmol/24 h (24.4%) lower in sodium reduction compared to usual care participants (P<0.0001), but only 21% of sodium reduction participants achieved the targeted level of sodium excretion below 80 mmol/24 h. Adherence was positively related to attendance at face-to-face contacts. Net decreases in SBP at 6, 18, and 36 months of 2.9 (P<0.001), 2.0 (P<0.001), and 1.3 (P=0.02) mmHg in sodium reduction vs usual care were associated with an overall 18% lower incidence of hypertension (P=0.048); were relatively unchanged by adjustment for ethnicity, gender, age, and baseline blood pressure, BMI, and sodium excretion; and were observed in both black and white men and women. From these beneficial but modest results with highly motivated and extensively counselled individuals, sodium reduction sufficient to favourably influence the population blood pressure distribution will be difficult to achieve without food supply changes.

Most ( approximately 70%) of strokes are first-ever strokes, and hence to substantially reduce the neurological burden, primary prevention is crucial. Here, highlights of the National Institute of Neurological Disorders and Stroke workshop "Stroke Risk Assessment and Future Stroke Primary Prevention Trials" held January 12-13, 2004 are summarized. The Workshop discussions focused on stroke risk assessment; the high-risk vs. population-based approaches to primary prevention; desirable characteristics of candidate treatments and potential novel treatments, such as the 'polypill'; subclinical disease as risk assessment tool and as surrogate outcome, and methodological issues in stroke primary prevention trials. The importance of assessing cognitive decline as an important consequence of covert and overt vascular injury of the brain was emphasized. The scientific or logistic barriers to stroke primary prevention trials are challenging, but are not insurmountable., (Copyright (c) 2005 S. Karger AG, Basel.)

This study aims to estimate the absolute number of persons with hypertension (the hypertension burden) and time trends using data from the National Health and Nutrition Examination Survey of United States resident adults who had hypertension in 1999 to 2000. This information is vitally important for health policy, medical care, and public health strategy and resource allocation. At least 65 million adults had hypertension in 1999 to 2000. The total hypertension prevalence rate was 31.3%. This value represents adults with elevated systolic or diastolic blood pressure, or using antihypertensive medications (rate of 28.4%; standard error [SE], 1.1), and adults who otherwise by medical history were told at least twice by a physician or other health professional that they had high blood pressure (rate of 2.9%; SE, 0.4). The number of adults with hypertension increased by approximately 30% for 1999 to 2000 compared with at least 50 million for 1988 to 1994. The 50 million value was based on a rate of 23.4% for adults with elevated blood pressure or using antihypertensive medications and 5.5% for adults classified as hypertensive by medical history alone (28.9% total; P<0.001). The approximately 30% increase in the total number of adults with hypertension was almost 4-times greater than the 8.3% increase in total prevalence rate. These trends were associated with increased obesity and an aging and growing population. Approximately 35 million women and 30 million men had hypertension. At least 48 million non-Hispanic white adults, approximately 9 million non-Hispanic black adults, 3 million Mexican American, and 5 million other adults had hypertension in 1999 to 2000.

We report a family in which the normal pattern of X-linked inheritance of hemophilia B (Factor IX deficiency) is complicated by mosaicism in the proband's maternal grandfather. The proband, an infant with severe Factor IX deficiency, was initially thought to be a sporadic case. Testing of other family members identified his mother as a carrier of the disorder, and his asymptomatic maternal grandfather as having very mild FIX deficiency. The causative familial mutation was identified as a two base pair deletion (AG within codons 134-135) in the Factor IX gene. The grandfather was shown to be "heterozygous" for the deletion. Karyotype analysis confirmed him to be 46XY thereby ruling out Klinefelter syndrome. The proband's aunt, who as the daughter of a man with hemophilia is theoretically an obligate carrier, was found not to carry this familial mutation, and thus not to be a carrier of hemophilia B. The grandfather must therefore be an X chromosome somatic and germline mosaic, with consequent segregation of the affected and non-affected Factor IX genes. This observation underlines the importance of confirming carrier status even in those individuals assumed to be obligate carriers, and has implications for genetic counseling.

The findings of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) have generated worldwide reaction from clinicians and researchers, including a recent commentary in this journal. Such response was expected for a trial of ALLHAT's size and scope, especially since its results challenged some widely held beliefs. This paper reviews key aspects of the ALLHAT design, analyses, findings, and conclusions to provide a perspective on the commentary about the trial's results and implications for clinical practice. Several of the most frequent comments regarding the study's results are addressed, particularly with respect to heart failure and diabetes outcomes. Responses to these comments reinforce the investigators' original conclusion that thiazide-type diuretics should remain the preferred first-step drug class for treating hypertension and should generally be a part of any multidrug regimen.

Context: The prevalence of overweight among children and adolescents increased between 1988 and 2000. The change in blood pressure among children and adolescents over that time and the role of overweight is unknown., Objective: To examine trends in systolic and diastolic blood pressure among children and adolescents between 1988 and 2000., Design, Setting, and Population: Two serially conducted cross-sectional studies using nationally representative samples of children and adolescents, aged 8 to 17 years, from the third National Health and Nutrition Examination Survey (NHANES III) conducted in 1988-1994 (n = 3496) and NHANES 1999-2000 (n = 2086)., Main Outcome Measures: Systolic and diastolic blood pressure levels., Results: In 1999-2000, the mean (SE) systolic blood pressure was 106.0 (0.3) mm Hg and diastolic blood pressure was 61.7 (0.5) mm Hg. After adjustment for age, mean systolic blood pressure was 1.6 mm Hg higher among non-Hispanic black girls (P =.11) and 2.9 mm Hg higher among non-Hispanic black boys (P<.001) compared with non-Hispanic whites. Among Mexican Americans, girls' systolic blood pressure was 1.0 mm Hg higher (P =.21) and boys' was 2.7 mm Hg higher (P<.001) compared with non-Hispanic whites (P<.001). With further adjustment for body mass index, these differences were attenuated. After age, race/ethnicity, and sex standardization, systolic blood pressure was 1.4 (95% confidence interval [CI], 0.6-2.2) mm Hg higher (P<.001) and diastolic blood pressure was 3.3 (95% CI, 2.1-4.5) mm Hg higher in 1999-2000 (P<.001) compared with 1988-1994. With further adjustment for differences in the body mass index distribution in 1988-1994 and 1999-2000, the increase in systolic blood pressure was reduced by 29% and diastolic blood pressure was reduced by 12%., Conclusions: Blood pressure has increased over the past decade among children and adolescents. This increase is partially attributable to an increased prevalence of overweight.

Although group characteristics are known to influence average blood pressure response to changes in salt intake, predictability of individual responses is less clear. We examined variability and consistency of individual systolic blood pressure responses to changes in salt intake in 188 participants who ate the same diet at higher, medium, and lower (140, 104, 62 mmol/d) sodium levels for 30 days each, in random order, after 2 weeks of run-in at the higher sodium level. Regarding variability in systolic blood pressure changes over time, changes from run-in to higher sodium (no sodium level change) ranged from -24 to +25 mm Hg; 8.0% of participants decreased > or =10 mm Hg. Regarding variability in systolic blood pressure response to change in sodium intake, with higher versus lower sodium levels (78-mmol sodium difference), the range of systolic blood pressure change was -32 to +17 mm Hg; 33.5% decreased > or =10 mm Hg. Regarding consistency of response, systolic blood pressure change with run-in versus lower sodium was modestly correlated with systolic blood pressure change with higher versus medium sodium; systolic blood pressure change with higher versus lower sodium was similarly correlated with run-in versus medium sodium (combined Spearman r=0.27, P=0.002). These results show low-order consistency of response and confirm that identifying individuals as sodium responders is difficult. They support current recommendations for lower salt intake directed at the general public rather than "susceptible" individuals as one of several strategies to prevent and control adverse blood pressures widely prevalent in the adult population.

Objective: The Women's Health Trial: Feasibility Study in Minority Populations (WHT: FSMP) documented that a low-fat diet was associated with a reduced fat intake in older women of diverse ethnic backgrounds. The purpose of the current study was to examine the effect of the low-fat diet on anthropometric and biochemical variables., Design: Randomized clinical trial in 2,208 postmenopausal women, 50 to 79 years of age., Results: The decrease in fat intake correlated directly with a decrease in body weight (r=.22, P<.001). After 6 months, the intervention group had an average weight loss of 1.8 kg. Body mass index decreased 0.7 kg/m2. Waist circumference decreased 1.8 cm. All of these changes were statistically significant, compared to changes in the control group (P<.01). Changes in systolic (-3.1 mm Hg) and diastolic (-1.1 mm Hg) blood pressures (BP) occurred in the intervention group. The decrease in systolic BP reached statistical significance (P=.02), relative to the control group. Decreases in plasma glucose were small (-0.2 mmol/L) in the intervention group, although there was a trend for difference from the control group (P=.11). Decreases in serum insulin levels were small (-0.5 microIU/mL) in the intervention group, although there was, again, a trend for difference from the control group., Conclusions: In older White, Black, and Hispanic women, a long-term low-fat dietary intervention was accompanied by modest, but statistically significant, decreases in body weight and anthropometric indices, without any particular attempt being made to reduce calories. Changes in glucose and insulin were small. The long-term biological significance of the glucose and insulin changes is unknown.

A Working Group on Research in Hypertension in Pregnancy was recently convened by the National Heart Lung and Blood Institute to determine the state of knowledge in this area and suggest appropriate directions for research. Hypertensive disorders in pregnancy, especially preeclampsia, are a leading cause of maternal mortality worldwide and even in developed countries increase perinatal mortality five-fold. Much has been learned about preeclampsia but gaps in the knowledge necessary to direct therapeutic strategies remain. Oxidative stress is a biologically plausible contributor to the disorder that may be amenable to intervention. Hypertension that antedates pregnancy (chronic hypertension) bears many similarities to hypertension in nonpregnant women but the special setting of pregnancy demands information to guide evidence based therapy. The recommendations of the Working Group are to attempt a clinical trial of antioxidant therapy to prevent preeclampsia that is be complemented by mechanistic research to increase understanding of the genetics and pathogenesis of the disorder. For chronic hypertension clinical trials are recommended to direct choice of drugs, evaluate degree of control and assess implications to the mother and fetus. Recommendations to increase participation in this research are also presented.

BACKGROUND: The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized, double-blind, active-controlled trial designed to compare the rate of coronary heart disease events in high-risk hypertensive participants initially randomized to a diuretic (chlorthalidone) versus each of three alternative antihypertensive drugs: alpha-adrenergic blocker (doxazosin), ACE-inhibitor (lisinopril), and calcium-channel blocker (amlodipine). Combined cardiovascular disease risk was significantly increased in the doxazosin arm compared to the chlorthalidone arm (RR 1.25; 95% CI, 1.17-1.33; P <.001), with a doubling of heart failure (fatal, hospitalized, or non-hospitalized but treated) (RR 2.04; 95% CI, 1.79-2.32; P <.001). Questions about heart failure diagnostic criteria led to steps to validate these events further. METHODS AND RESULTS: Baseline characteristics (age, race, sex, blood pressure) did not differ significantly between treatment groups (P <.05) for participants with heart failure events. Post-event pharmacologic management was similar in both groups and generally conformed to accepted heart failure therapy. Central review of a small sample of cases showed high adherence to ALLHAT heart failure criteria. Of 105 participants with quantitative ejection fraction measurements provided, (67% by echocardiogram, 31% by catheterization), 29/46 (63%) from the chlorthalidone group and 41/59 (70%) from the doxazosin group were at or below 40%. Two-year heart failure case-fatalities (22% and 19% in the doxazosin and chlorthalidone groups, respectively) were as expected and did not differ significantly (RR 0.96; 95% CI, 0.67-1.38; P = 0.83). CONCLUSION: Results of the validation process supported findings of increased heart failure in the ALLHAT doxazosin treatment arm compared to the chlorthalidone treatment arm.

Context: Blood pressure control (<140/90 mm Hg) rates for hypertension fall far short of the US national goal of 50% or more. Achievable control rates in varied practice settings and geographic regions and factors that predict improved blood pressure control are not well identified., Objective: To determine the success and predictors of blood pressure control in a large hypertension trial involving a multiethnic population in diverse practice settings., Design: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial is a randomized, double-blind, active-controlled clinical trial with a mean follow-up of 4.9 years. Participant enrollment began in February 1994 and follow-up was completed in March 2002., Setting: A total of 623 centers in the United States, Canada, and the Caribbean., Participants: A total of 33,357 participants (aged > or =55 years) with hypertension and at least one other coronary heart disease risk factor., Interventions: Participants were randomly assigned to receive (double-blind) chlorthalidone, 12.5-25 mg/d (n=15,255), amlodipine 2.5-10 mg/d (n=9048), or lisinopril 10-40 mg/d (n=9054) after other medication was discontinued. Doses were increased within these ranges and additional drugs from other classes were added as needed to achieve blood pressure control (<140/90 mm Hg)., Main Outcome Measures: The outcome measures for this report are systolic and diastolic blood pressure, the proportion of participants achieving blood pressure control (<140/90 mm Hg), and the number of drugs required to achieve control in all three groups combined., Results: Mean age was 67 years, 47% were women, 35% black, 36% diabetic; 90% were on antihypertensive drug treatment at entry. At the first of two pre-randomization visits, blood pressure was <140/90 mm Hg in only 27.4% of participants. After 5 years of follow-up, the percent controlled improved to 66%. Systolic blood pressure was <140 mm Hg in 67% of participants, diastolic blood pressure was <90 mm Hg in 92%, the mean number of drugs prescribed was 2.0+/-1.0, and the percent on > or =2 drugs was 63%. Blood pressure control varied by geographic regions, practice settings, and demographic and clinical characteristics of participants., Conclusions: These data demonstrate that blood pressure may be controlled in two thirds of a multiethnic hypertensive population in diverse practice settings. Systolic blood pressure is more difficult to control than diastolic blood pressure, and at least two antihypertensive medications are required for most patients to achieve blood pressure control. It is likely that the majority of people with hypertension could achieve a blood pressure <140/90 mm Hg with the antihypertensive medications available today., (Copyright 2002 Le Jacq Communications, Inc.)

The National High Blood Pressure Education Program Coordinating Committee published its first statement on the primary prevention of hypertension in 1993. This article updates the 1993 report, using new and further evidence from the scientific literature. Current recommendations for primary prevention of hypertension involve a population-based approach and an intensive targeted strategy focused on individuals at high risk for hypertension. These 2 strategies are complementary and emphasize 6 approaches with proven efficacy for prevention of hypertension: engage in moderate physical activity; maintain normal body weight; limit alcohol consumption; reduce sodium intake; maintain adequate intake of potassium; and consume a diet rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat. Applying these approaches to the general population as a component of public health and clinical practice can help prevent blood pressure from increasing and can help decrease elevated blood pressure levels for those with high normal blood pressure or hypertension.

Hemophilia A is a bleeding disorder caused by a quantitative or qualitative deficiency in the coagulation factor VIII. Causative mutations are heterogeneous in nature and are distributed throughout the FVIII gene. With the exception of mutations that result in prematurely truncated protein, it has proved difficult to correlate mutation type/amino acid substitution with severity of disease. We have identified 81 mutations in 96 unrelated patients, all of whom have typed negative for the common IVS-22 inversion mutation. Forty-one of these mutations are not recorded on F8C gene mutation databases. We have analyzed these 41 mutations with regard to location, whether or not each is a cross-species conserved region, and type of substitution and correlated this information with the clinical severity of the disease. Our findings support the view that the phenotypic result of a mutation in the FVIII gene correlates more with the position of the amino acid change within the 3D structure of the protein than with the actual nature of the alteration., (Copyright 2002 Wiley-Liss, Inc.)

A simple, rapid and cost-effective method for the analysis of three of the most widely screened genetic risk factors for thrombosis has been established. The protocol developed uses blood spots stored on filter paper (Guthrie spots) as well as DNA extracted from anticoagulated blood. The use of Guthrie spots taken at birth enables the retrospective study of patients who develop thrombotic complications without necessitating resampling. Following isolation of DNA, conventional fluorescence-labelled polymerase chain reaction (PCR) is performed using a thermostable DNA polymerase. Denatured, single-stranded PCR products are analysed on a semi-automated capillary-based genetic analyser, the data being stored electronically. This sensitive protocol obviates the need for endonuclease digestion and the associated gel running and documentation, and leads to a reduction in the recurrent costs of laboratory consumables.

A nested case-control study was undertaken involving men participating in the Multiple Risk Factor Intervention Trial (MRFIT). Serum samples from 712 men, stored for upto 20 years, were analysed for homocyst(e)ine. Cases involved non-fatal myocardial infractions, identified through the active phase of the study, which ended on February 28, 1982, and deaths due to coronary heart disease, monitored through 1990. The non-fatal myocardial infarction occurred within 7 years of sample collection, whereas the majority of coronary heart disease deaths occurred more than 11 years after sample collection. Mean homocyst(e)ine concentrations were in the expected range and did not differ significantly between case patients and control subjects: myocardial infarction cases, 12.6 micromol/L; myocardial infarction controls, 13.1 micromol/L; coronary heart disease death cases, 12.8 micromol/L; and coronary heart disease controls, 12.7 micromol/L. Odds ratios versus quartile 1 for coronary heart disease deaths and myocardial infarctions combined were as follows: quartile 2, 1.03; quartile 3, 0.84; and quartile 4, 0.92. Thus, in this prospective study, no association of homocyst(e)ine concentration with heart disease was detected. Homocyst(e)ine levels were weakly associated with the acute-phase (C-reactive) protein. These results are discussed with respect to the suggestion that homocyst(e)ine is an independent risk factor for heart disease.

We report a case of spontaneous left pulmonary artery thrombosis in a 3-day-old male neonate. The presentation of heparin resistance and thrombosis raised the possibility of a type II heparin binding site antithrombin deficiency. A continuous infusion of antithrombin concentrate was used successfully, following failure of plasma, to correct the heparin resistance. Rapid genetic analysis allowed sequencing of the antithrombin gene within 5 working days. This showed the infant to be homozygous for the substitution of C to T at nucleotide 2759. This base change causes mutation of the native leucine at codon 99 to a phenylalanine. This antithrombin variant has been previously reported (antithrombin Budapest 3) and results in reduced binding of heparin to antithrombin. Such a molecular diagnostic approach is feasible and warranted in such cases of neonatal thrombosis because of the diagnostic difficulties encountered.

Background: Populations eating mainly vegetarian diets have lower blood pressure levels than those eating omnivorous diets. Epidemiologic findings suggest that eating fruits and vegetables lowers blood pressure., Hypothesis: Two hypotheses were tested: (1) that high intake of fruits and vegetables lowers blood pressure, and (2) that an overall dietary pattern (known as the DASH diet, or DASH combination diet) that is high in fruits, vegetables, nuts, and low-fat dairy products, emphasizes fish and chicken rather than red meat, and is low in saturated fat, cholesterol, sugar, and refined carbohydrate lowers blood pressure., Methods: Participants were 459 adults with untreated systolic blood pressure < 160 mmHg and diastolic blood pressure 80-95 mmHg. After a 3-week run-in on a control diet typical of Americans, they were randomized to 8 weeks receiving either the control diet, or a diet rich in fruits and vegetables, or the DASH diet. The participants were given all of their foods to eat, and body weight and sodium intake were held constant. Blood pressure was measured at the clinic and by 24-h ambulatory monitoring., Results: The DASH diet lowered systolic blood pressure significantly in the total group by 5.5/3.0 mmHg, in African Americans by 6.9/3.7 mmHg, in Caucasians by 3.3/2.4 mmHg, in hypertensives by 11.6/5.3 mmHg, and in nonhypertensives by 3.5/2.2 mmHg. The fruits and vegetables diet also reduced blood pressure in the same subgroups, but to a lesser extent. The DASH diet lowered blood pressure similarly throughout the day and night., Conclusions: The DASH diet may offer an alternative to drug therapy in hypertensives and, as a population approach, may prevent hypertension, particularly in African Americans.

From a world-wide, population perspective, the problem of excessive blood pressure levels for optimal cardiovascular health is immense and growing. Evidence from animal experimentation, observational epidemiology, and randomized clinical trials strongly supports efforts to change nutritional factors in desirable directions, especially to lower dietary salt and increase potassium intake.

Background: National guidelines recommend consideration of step down or withdrawal of medication in patients with well-controlled hypertension, but knowledge of factors that predict or mediate success in achieving this goal is limited., Objective: To identify patient characteristics associated with success in controlling blood pressure (BP) after withdrawal of antihypertensive medication., Design: The Trial of Nonpharmacologic Interventions in the Elderly tested whether lifestyle interventions designed to promote weight loss or a reduced intake of sodium, alone or in combination, provided satisfactory BP control among elderly patients (aged 60-80 years) with hypertension after withdrawal from antihypertensive drug therapy. Participants were observed for 15 to 36 months after attempted drug withdrawal., Main Outcome Measures: Trial end points were defined by (1) a sustained BP of 150/90 mm Hg or higher, (2) a clinical cardiovascular event, or (3) a decision by participants or their personal physicians to resume BP medication., Results: Proportional hazards regression analyses indicated that the hazard (+/- SE) of experiencing an end point among persons assigned to active interventions was 75% +/- 9% (weight loss), 68% +/- 7% (sodium reduction), and 55% +/- 7% (combined weight loss/sodium reduction) that of the hazard for those assigned to usual care. Lower baseline systolic BP (P < .001), fewer years since diagnosis of hypertension (P < .001), fewer years of antihypertensive treatment (P < .001), and no history of cardiovascular disease (P = .01) were important predictors of maintaining successful nonpharmacological BP control throughout follow-up, based on logistic regression analysis. Age, ethnicity, baseline level of physical activity baseline weight, medication class, smoking status, and alcohol intake were not statistically significant predictors. During follow-up, the extent of weight loss (P = .001) and urinary sodium excretion (P = .04) were associated with a reduction in the risk of trial end points in a graded fashion., Conclusions: Withdrawal from antihypertensive medication is most likely to be successful in patients with well-controlled hypertension who have been recently (within 5 years) diagnosed or treated, and who adhere to life-style interventions involving weight loss and sodium reduction. More than 80% of these patients may have success in medication withdrawal for longer than 1 year.

The angiotensinogen gene has been linked to essential hypertension and increased blood pressure. A functional variant believed to be responsible for hypertension susceptibility occurs at position -6 in the promoter region of the gene in which an A for G base pair substitution is associated with higher angiotensinogen levels. To test whether an allele within the angiotensinogen gene is related to subsequent incidence of hypertension and blood pressure response to sustained sodium reduction, 1509 white male and female subjects participating in phase II of the Trials of Hypertension Prevention were genotyped at the angiotensinogen locus. Participants had diastolic blood pressures between 83 and 89 mm Hg and were randomized in a 2x2 factorial design to sodium reduction, weight loss, combined intervention, or usual care groups. Persons in the usual care group with the AA genotype at nucleotide position -6 had a higher 3-year incidence rate of hypertension (44.6%) compared with those with the GG genotype (31.5%), with a relative risk of 1.4 (95% confidence interval [0.87, 2.34], test for trend across all 3 genotypes, P=0.10). In contrast, the incidence of hypertension was significantly lower after sodium reduction for persons with the AA genotype (relative risk=0.57 [0.34, 0.98] versus usual care) but not for persons with the GG genotype (relative risk=1.2 [0.79, 1.81], test for trend P=0.02). Decreases of diastolic blood pressure at 36 months in the sodium reduction group versus usual care showed a significant trend across all 3 genotypes (P=0.01), with greater net blood pressure reduction in those with the AA genotype (-2.2 mm Hg) than those with the GG genotype (+1.1 mm Hg). A similar trend across the 3 genotypes for net systolic blood pressure reduction (-2.7 for AA versus -0.2 mm Hg for GG) was not significant (P=0.17). Trends across genotypes for the effects of weight loss on hypertension incidence and decreases in blood pressure were similar to those for sodium reduction. We conclude that the angiotensinogen genotype may affect blood pressure response to sodium or weight reduction and the development of hypertension.

Intraperson variability in both blood pressure (BP) and sodium excretion dilutes associations and leads to underestimates of the dose-response relation. The authors applied statistical correction techniques to data from the Trials of Hypertension Prevention (TOHP), Phase I, carried out 1987-1990. Men and women with high normal diastolic BP (80-89 mmHg) were randomized to sodium reduction (n = 327) or a usual care comparison group (n = 417). Regression estimates of the effects of change in sodium and sodium/potassium ratio (Na/K ratio) on blood pressure change in the pooled sample were corrected for both the within-person variance of the excretion measures and the within-person covariance with blood pressure using a multivariate error correction. The estimated cross-sectional reliability was 0.36 for square root(Na) and 0.42 for square root(Na/K ratio) and that for change was 0.31 and 0.28, respectively. Corrected coefficients suggested a decrease of 4.4 mmHg in systolic BP (95% confidence interval (CI) 0.1-8.8) and 2.8 mmHg in diastolic BP (95% CI -0.2 to 5.8) per 100 mmol/24 hour reduction in sodium, and of 3.4 mmHg in systolic BP (95% CI 0.8-6.1) and 1.7 mmHg in diastolic BP (95% CI 0.0-3.5) per unit decrease in Na/K. These results are comparable with those from the Intersalt Study, and suggest that the true effect of sodium change on blood pressure change in normotensives over 18 months is underestimated by more than half in uncorrected data.

A nested case-control study was undertaken involving men participating in the Multiple Risk Factor Intervention Trial (MRFIT). Serum samples from 712 men, stored for up to 20 years, were analyzed for homocyst(e)ine. Cases involved nonfatal myocardial infarctions (MIs), identified through the active phase of the study, which ended on February 28, 1982, and deaths due to coronary heart disease (CHD), monitored through 1990. The nonfatal MIs occurred within 7 years of sample collection, whereas the majority of CHD deaths occurred more than 11 years after sample collection. Mean homocyst(e)ine concentrations were in the expected range and did not differ significantly between case patients and control subjects: MI cases, 12.6 mumol/L; MI controls, 13.1 mumol/L; CHD death cases, 12.8 mumol/L; and CHD controls, 12.7 mumol/L. Odds ratios versus quartile 1 for CHD deaths and MIs combined were as follows: quartile 2, 1.03; quartile 3, 0.84; and quartile 4, 0.92. Thus, in this prospective study, no association of homocyst(e)ine concentration with heart disease was detected. Homocyst(e)ine levels were weakly associated with the acute-phase protein (C-reactive protein). These results are discussed with respect to the suggestion that homocyst(e)ine is an independent risk factor for heart disease.

Current dietary guidance includes a recommendation for moderate reduction of sodium (Na) intake of US adults to less than 2400 mg (approximately 100 mmol) per day. The safety of this recommendation tends to be taken for granted, but questions are raised periodically about possible adverse effects. We evaluated the evidence available to address these concerns. Relevant sources were identified through review of policy documents and a systematic MEDLINE search of articles published between 1984 and mid-October 1995. Reviews and commentaries were selected to encompass the spectrum of arguments for or against possible adverse effects. All identified randomized, human intervention trials of Na reduction with at least 6 months' follow up and urinary Na excretion data were included; selected additional evidence was evaluated as needed to address specific issues. Reports of trials were abstracted to describe relevant design features, study populations, level of Na reduction, and comments or data relevant to adverse effects. We found that some concerns were based on short-term, Na-depletion studies and were, therefore, not relevant to moderate Na reduction in the population-at-large. Other concerns were largely speculative and, from our review, were not supported by the combined evidence from 20 randomized Na reduction trials conducted in varied clinical or community settings and involving diverse populations followed for up to 5 years. Overall, we identified extensive data supporting the safety of public health recommendations for moderate Na reduction and none suggesting cause for concern.

The highlights of each generation of hypertension trials have been varied, but interrelated. The initial hypertension trials focused on middle-aged hypertensive individuals and later on the elderly, with emphasis on diastolic blood pressure and subsequently on systolic blood pressure. Past generations of trials elucidated whether and whom to treat. The current explosion of morbidity and mortality trials in hypertension largely seeks to learn what drugs should be used and to delineate what blood pressure goals should be targeted.

Purpose: The Multiple Risk Factor Intervention Trial (MRFIT), a randomized clinical trial for the primary prevention of coronary heart disease, enrolled 12,866 men (including 8194 cigarette smokers) aged 35-57 years at 22 clinical centers across the United States. Participants were randomized either to special intervention (SI), which included an intensive smoking cessation program, or to usual care (UC). After 16 years of follow-up, lung cancer mortality rates were higher in the SI than in the UC group. Since rates of smoking cessation in SI were higher than those for UC for the 6 years of the trial, and since risk of lung cancer mortality is known to decline with smoking cessation, these results were unexpected. The purpose of the present study was to investigate hypotheses that could explain the higher observed lung cancer mortality rates in the SI as compared with the UC group., Methods: Analytic methods were employed to determine whether SI and UC participants differed either in baseline characteristics or in characteristics that changed during the trial and to determine whether these differences could explain the higher rates of lung cancer mortality among SI as compared to UC participants. Rates of mortality from coronary heart (CHD) were examined to explore the possibility that prevention of CHD death may have contributed to greater mortality due to lung cancer in the SI group., Results: From randomization through December 1990, 135 SI and 117 UC participants died from lung cancer. The relative difference between the SI and U groups adjusted for age and number of cigarettes smoked per day, was 1.17 (95% CI:0.92-1.51). The greatest difference between the SI and UC groups in lung cancer mortality rates occurred among the heaviest smokers at baseline who did not achieve sustained smoking cessation by year 2. In this group the rates of death from CHD were approximately the same among the SI and UC subjects. No differences in baseline characteristics were found between SI and UC smokers who did not achieve sustained cessation by year 2, and there were no differences in follow-up characteristics between the two study groups that could explain the difference in lung cancer mortality., Conclusions: None of the hypotheses proposed to explain the unexpected higher rates of lung cancer mortality among SI as compared with UC subjects were sustained by the data. Thus we conclude that the difference observed is due to chance, and that a longer period of sustained smoking cessation plus follow-up is necessary to detect a reduction in lung cancer mortality as a result of smoking cessation intervention in a randomized clinical trial.

Background: Findings from numerous epidemiologic and clinical studies worldwide attest to a strong, graded, consistent relationship between blood pressure level and cardiovascular-renal diseases, subclinical and clinical, nonfatal and fatal., Objective: This review summarizes results from selected prospective observational studies, primarily from US populations, and from randomized clinical trials. Review Analyses from the Multiple Risk Factor Intervention Trial (MRFIT) subjects (middle-aged men) and the Framingham Heart Study (middle-aged and elderly men and women) clearly establish that systolic blood pressure is a more powerful predictor of cardiovascular events than diastolic pressure. Wherever the full range of blood pressure has been examined, for example for systolic pressure in the MRFIT subjects and for diastolic pressure in pooled data from nine epidemiologic studies, the associations for coronary heart disease and stroke are seen to extend over the whole range, including 'normotensive' levels. In MRFIT, this continuous relationship has also recently been shown for end-stage renal disease and both systolic and diastolic pressure. Data from Framingham document further associations with peripheral vascular disease, congestive heart failure, and both electrocardiographic and echocardiographic left ventricular hypertrophy. Several studies are row available demonstrating a relationship between hypertension and carotid wall intimal-medial thickness. Finally, the causal nature of the relationships with major cardiovascular events is supported by the results of 17 large-scale randomized trials of blood-pressure-lowering using primarily diuretic- and beta-blocker-based drug regimens., Conclusions: These trials have demonstrated highly significant reductions in fatal and nonfatal stroke and major coronary heart disease. There are few trial data, however, on health benefits from further reducing blood pressure among normotensive persons.

Background: Elevated blood pressure remains a widespread major impediment to health. Obesity and specific dietary factors such as high salt and alcohol intake and low potassium intake adversely affect blood pressure. It is a reasonable hypothesis that additional dietary constituents, particularly macronutrients, may also influence blood pressure., Methods and Results: Participants were 11,342 middle-aged men from the Multiple Risk Factor Intervention Trial (MRFIT). Data from repeat 24-hour dietary recalls (four to five per person) and blood pressure measurements at six annual visits were used to assess relationships, singly and in combination, of dietary macronutrients to blood pressure, adjusted for multiple possible confounders (demographic, dietary, and biomedical). Multiple linear regression was used to assess diet-blood pressure relations in two MRFIT treatment groups (special intervention and usual care), with adjustment for confounders, pooling of coefficients from the two groups (weighted by inverse of variance), and correction of coefficients for regression-dilution bias. In multivariate regression models, dietary cholesterol (milligrams per 1000 kilocalories), saturated fatty acids (percent of kilocalories), and starch (percent of kilocalories) were positively related to blood pressure; protein and the ratio of dietary polyunsaturated to saturated fatty acids were inversely related to blood pressure. These macronutrient-blood pressure findings were obtained in analyses that controlled for body mass, dietary sodium and ratio of sodium to potassium, and alcohol intake, each positively related to blood pressure, and intake of potassium and caffeine, both inversely related to blood pressure., Conclusions: These data support the concept that multiple dietary factors influence blood pressure; hence, broad improvements in nutrition can be important in preventing and controlling high-normal and high blood pressure.

Detection, treatment and control of hypertension is one of the best proven approaches to prevention of cardiovascular disease. Antihypertensive treatment trials have convincingly demonstrated that diuretics and beta-blockers reduce the risk of stroke and coronary heart disease. Corresponding information is not yet available for newer classes of antihypertensive drug therapy such as calcium channel blockers, angiotensin converting enzyme inhibitors and alpha 1 receptor blockers. Several experimental studies are now addressing this question. The largest such trial (n = 40,000) is the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). This manuscript describes two studies (TOMHS and the VA study on antihypertensive agents) that compared several classes of antihypertensive drugs with regard to blood pressure outcomes and ALLHAT, which is comparing the effect of four first-step approaches to antihypertensive therapy on combined incidence of fatal coronary heart disease and non-fatal myocardial infarction.

Are newer types of antihypertensive agents, which are currently more costly to purchase on average, as good or better than diuretics in reducing coronary heart disease incidence and progression? Will lowering LDL cholesterol in moderately hypercholesterolemic older individuals reduce the incidence of cardiovascular disease and total mortality? These important medical practice and public health questions are to be addressed by the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind trial in 40,000 high-risk hypertensive patients. ALLHAT is designed to determine whether the combined incidence of fatal coronary heart disease (CHD) and nonfatal myocardial infarction differs between persons randomized to diuretic (chlorthalidone) treatment and each of three alternative treatments--a calcium antagonist (amlodipine), an angiotensin converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin). ALLHAT also contains a randomized, open-label, lipid-lowering trial designed to determine whether lowering LDL cholesterol in 20,000 moderately hypercholesterolemic patients (a subset of the 40,000) with a 3-hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor, pravastatin, will reduce all-cause mortality compared to a control group receiving "usual care." ALLHAT's main eligibility criteria are: 1) age 55 or older; 2) systolic or diastolic hypertension; and 3) one or more additional risk factors for heart attack (eg, evidence of atherosclerotic disease or type II diabetes). For the lipid-lowering trial, participants must have an LDL cholesterol of 120 to 189 mg/dL (100 to 129 mg/dL for those with known CHD) and a triglyceride level below 350 mg/dL. The mean duration of treatment and follow-up is planned to be 6 years. Further features of the rationale, design, objectives, treatment program, and study organization of ALLHAT are described in this article.

Body mass is a major factor in determining blood pressure levels in children. We compared associations of body mass with blood pressure in 121 white and 91 black children in Bogalusa, Louisiana with that of 370 children in Kangwha, Korea. All children were seven years old at entry into the study and were followed for three years. Korean children were shorter (p < 0.001) thinner (p <0.0001), and had a lower body mass index (p < 0.01) than white or black children. At age seven, systolic blood pressure levels were 2 approximately 5 mm Hg lower, but at age 10, they were 2 approximately 5 mm Hg higher in Korean than white or black children. The increases in blood pressure levels from age seven to ten years were much greater in Korean than black or white children, while changes in height, weight, and body mass index were generally less. Change in blood pressure level was positively associated with change in body mass index for systolic (but not diastolic) levels; however, the association was no stronger for Korean than for U.S. children, except for Korean males vs Bogalusa black males. Cross-cultural studies of other factors, such as diet and physical activity, may explain these differences.

The objectives of the study were to assess whether the epidemiologic data support a relation between dietary calcium intake and blood pressure, to obtain a quantitative estimate of the difference in blood pressure for a given difference in dietary calcium intake, and to assess the public health implications. A meta-analysis of published data (January 1983 to November 1993) that investigated the association between dietary calcium intake and blood pressure in different populations around the world was performed. Of 63 population studies identified, 23 were suitable for a quantitative overview (total n = 38,950). Unadjusted regression coefficients (95% confidence intervals) were obtained. Pooled unadjusted regression coefficients (95% confidence intervals) were then computed weighting each individual study by the inverse of its variance. Tests of heterogeneity and sensitivity analysis were carried out, and the possibility of publication bias was assessed. The regression coefficients ranged between -9.40 and 1.63 mmHg/100 mg calcium for systolic blood pressure and between -4.90 and 0.47 for diastolic blood pressure. In men (11 studies, n = 7,271), the pooled regression coefficients were -0.010 and -0.009 mmHg/100 mg calcium for systolic and diastolic pressures, respectively (p < 0.001 and p < 0.05). In women (six studies, n = 8,507), they were -0.15 and -0.057 mmHg/100 mg calcium (p < 0.001 and p < 0.02), and in men and women combined (six studies, n = 23,172 for systolic pressure and four studies, n = 3,215 for diastolic pressure) they were -0.061 and -0.061 mmHg/100 mg calcium (p < 0.001 and p < 0.05). In those studies that used the 24-hour recall method, the pooled regression coefficients were -0.06 and -0.09 mmHg/100 mg calcium (p < 0.005 and p = 0.07), whereas in those that used the food frequency questionnaire, they were -0.15 and -0.05 mmhg/100 mg calcium (p < 0.001 and p < 0.03). These data are consistent with an inverse association between dietary calcium intake and blood pressure. However, the size of the estimate, the observed heterogeneity among studies, and the possibility of confounding and publication bias indicate that an increase in calcium intake above the Recommended Dietary Allowance is not recommended at population level for the prevention and treatment of high blood pressure.